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Background

The use of the lipid-lowering agent niacin is hampered by a frequent flush response
which is largely mediated by prostaglandin (PG) D2. Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist
laropiprant has been proposed to be a useful approach in preventing niacin-induced
flush. However, antagonizing PGD2, which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic
events in cardiovascular disease. Therefore, we investigated the effects of laropiorant
on platelet function.

Methods

Platelet aggregation assays were performed ex vivo using a platelet aggregation analyser (Aggregometer II). Blood from healthy human
donors was used to obtain platelet-rich plasma. The expression of P-selectin and activation
of glycoprotein IIb/IIIa was examined using CD62P and PAC1 antibodies, respectively,
by direct flow cytometry. In vitro thrombus formation was assessed by flowing whole blood on collagen-coated Cellix
biochips at −30 dyn/cm2 using the Mirus nanopump.

Results

In vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD2 on platelet function, i.e. platelet aggregation, P-selectin expression, activation of glycoprotein IIb/IIIa
and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects
of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations,
laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and
E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet
aggregation, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition
of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant.

Conclusions

These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have
a beneficial profile with respect to platelet function and thrombotic events in vascular
disease.

Acknowledgements

S.P. was funded by the PhD Program Molecular Medicine of the Medical University of
Graz. This study was supported by the Jubiläumsfonds of the Austrian National Bank
(OeNB, grants 13487 and 14263) and the Austrian Science Fund (FWF; grants P22521-B18,
P19473-B05, P21004-B02 and P22976-B18).